大腦白質受損所引起的腦傷佔早產兒腦部病變之大部份，同時合併腦神經發育不良。根據統計顯示出生體重小於1500公克之早產兒，約有10%出現合併腦性麻痺以及50%罹患認知及行為缺陷的疾病。大腦周腦室白質軟化症主要是由大腦深部白質受損所引起的腦傷。大腦周腦室白質軟化症成因包括oligodendrocyte之受損 astrogliosis 及小膠質細胞之活化。這些因素造成大腦白質局部或廣泛性傷害，導致大腦後期的腦室擴大。目前CXCL5 被證實與成人之急性缺血性腦病變之急性發炎期中佔有重要角色，也被證實與早產及胎內感染有關。因此我們假設 CXCL5於早產兒之大腦周腦室白質軟化症中佔有重要之角色。
我們之前的研究已建立了一種，脂多醣合併缺氧窒息的幼鼠大腦白質受損疾病的模式，於出生第二天之新生鼠給予低劑量脂多醣(0.05mg/kg)及缺氧窒息會引起大腦白質發炎導致白質病變。我們利用此老鼠疾病模式探CXCL5與大腦白質病變之關係。於Western blot檢驗發現於缺氧窒息6小時及24小時，CXCL5表現有增加。於缺氧窒息24小時腦部切片，觀察CXCL5的表現於受損白質有增加的現象。螢光免疫染色顯示白質小膠質細胞為主要分泌CXCL5之細胞，而在灰質主要以neuron為主要分泌CXCL5之細胞。我們進一步發現缺氧前2小時給予腦內注射CXCL5 取代LPS 於幼鼠大腦白質受損疾病的模式，於幼鼠11天大時，觀察腦部切片發現有MBP蛋白表現降低及astrogliosis及大腦腦室擴大，相較於NS+HI或對照組NS組別。於缺氧24小時觀察腦部切片發現，腦內注射CXCL5合併缺氧窒息會導致血腦屏障受損、小膠質細胞活化及嗜中性白血球浸潤。腦內注射CXCL5無合併缺氧窒息組別，只導致血腦屏障受損及嗜中性白血球浸潤但無小膠質細胞活化。
根據上述結果，我們認為CXCL5在幼鼠大腦白質受損疾病中扮演非常重要之致病角色。我們的實驗結果更加証明了CXCL5會造成具有幼鼠大腦白質受損， 同時具有臨床上診斷及治療早產兒白質受傷藥物之前瞻性。

Cerebral white matter injury (WMI) is the most common form of injury in the preterm infants, and is associated with subsequent neurodevelopmental impairment. Among the survivors of very-low-birth-weight infants, 10% exhibit cerebral palsy, and 50% have cognitive/behavioral deficits. Periventricular leukomalacia (PVL) is the major form of white matter injury, characterized by loss of premyelinating oligodendrocytes (pre-OLs), astrogliosis, and microglial infiltration. Increased CXCL5 expression has been found in preterm infants with intrauterine infection. Using an established model of selective white matter injury in postpartum (P) day 2 rat pups induced by lipopolysaccharide (LPS) followed by hypoxic ischemia (HI), we hypothesized that CXCL5 is involved in the white matter injury of the immature brain.
We found that P2 rat pups had increased CXCL5 expression in the cerebral cortex compared with P7 and P30 rats. All the P3, P7 and P30 rats had very few CXCL5 expression in the white matter. Immunofluorescence showed that CXCL5 was mainly expressed in cortical neurons of P2 pups. Western blots demonstrated increases of CXCL5 levels in the cortex 6 h to 24 h after hypoxia in the LPS+HI pups. Immunohistochemical analysis showed increased CXCL5 immunoreactivity in the white matter 24 h after HI in the LPS+HI group. Immunofluorescence showed that CXCL5 was mainly expressed in the CD11b+ microglia in the white matter and neurons in the cortex.
To confirm that CXCL5 sensitized HI-induced white matter injury, we intracerebroventricularly injected recombinant CXCL5 (2 ug per rat) to P2 rat pups before HI. On P11, the CXCL5+HI but not the NS+HI group had significant decreases of myelin basic protein (MBP) expression, increases of astrocytosis in the white matter, and increases of ventricle size but without neuronal injury in the ipsilateral hemisphere compared with the NS group. The CXCL5 group also had significant decreases of MBP in the white matter. In addition, the CXCL5+HI group had significant increases of blood-brain barrier damage evidenced by increases of extravascular IgG leakage, and increases of microglia and neutrophil infiltration in the white matter than the NS group. The CXCL5 group had more blood-brain barrier damage and upregulated neutrophil but not microglia infiltration in the white matter than the NS group.
In the immature brain, CXCL5 followed by HI upregulates microglia and neutrophils infiltration, and causes white matter injury, while CXCL5 alone predominately induces neutrophil infiltration and also causes white matter injury. Targeting on CXCL5 and its receptor signaling may be an attractive therapeutic strategy to protect against white matter injury in the immature brain.

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